System for describing the physical distribution of an agent in a patient

ABSTRACT

A system for describing the physical distribution of an agent that accumulates selectively in tissue of a patient in an excised surgical specimen. The system comprises an agent which selectively concentrates in a cancer or precancer or focus of infection or other pathological condition. The system comprises a detector sensitive to the agent which is present in the surgical specimen. The system also comprises an apparatus capable of forming an image based on the information gathered by the detector, and which image describes the physical distribution of the agent in the surgical specimen so that a surgeon can be guided by the image provided by the apparatus, said apparatus connected to said detector.

FIELD OF THE INVENTION

[0001] The present invention relates to the field of surgical pathology,in which a pathologist attempts to convey to a surgeon as rapidly aspossible the presence and distribution of cancer in a resected surgicalspecimen. In particular, the present invention utilizes the biochemicalspecificity of injectable materials such as radiotracers with digitalautoradiography techniques to image the specimen immediately aftersurgical resection.

BACKGROUND OF THE INVENTION

[0002] Current surgical pathology practice consists of having apathologist receive a surgical specimen immediately after resection. Thepathologist marks the specimen with ink to show how the specimen wasoriented in the body (i.e., the blue-inked side was facing forward inthe body). The pathologist then slices the specimen into thin (i.e., 3mm thick) slices, and visually inspects the slices. The pathologist thenselects the areas that appear visually to have the greatest likelihoodof containing cancer, and removes a small section from these pieces. Thepathologist freezes these small pieces and shaves thin sections forrapid staining and inspection under a microscope (“frozen section”). Thepathologist conveys his or her impression as to the frozen sectionresults to the surgeon, so that the surgeon can decide whether theresection has been adequate. If the frozen section examination suggeststhat the cancer cells are very close to the margin of the surgicalspecimen, the surgeon is alerted that the “margins are not clear” andthat additional tissue needs to be removed to insure that the entirecancer is gone from the body. Theoretically, the surgeon could have thepatient ready on the operating room table for additional removal oftissue pending the pathologists' opinion as to whether this additionalremoval is needed. In practice, because frozen section examination isfairly inaccurate, most surgeons will not rely on the information fromfrozen section examination, and will simply complete their surgery andhope that when the final pathological report comes out (several daysafter surgery) the margins will have been shown to be clear of tumor.The risk of local recurrence of breast cancer is higher if the marginsare not clear and if re-excision is not done. As a result, for breastcancer resections, in as many as 30% of cases, a re-excision is neededbecause the final pathology report comes back saying that the marginswere not clear.

[0003] The present invention also pertains to the art ofautoradiography. Autoradiography is a very old technique for usingradiotracers in tissues to form images of radiotracer concentration inthe tissues. Autoradiography is typically performed by injecting ananimal with a radioactive tracer, sacrificing the animal, and thenslicing the animal's organs up and imaging the sliced organs with adetector that is sensitive to radiation emitted by the radioactivetracer. In nearly all cases, the autoradiography detector is sensitiveto beta rays emitted by a radioactive tracer. The notable feature ofautoradiography is that the specimen is placed in contact with theradiation detector, thereby improving spatial resolution.

[0004] The present invention also pertains to the art of radiotracerimaging of human cancers. Radiotracers consists of a chemical compoundcontaining a component that is biologically specific (i.e., binds to aspecific type of receptor, cell or organ), and a second component thatemits radiation which can be detected by a device placed external to thebody. For breast cancer imaging, the most widely used radiotracers arethe positron-emitter 2-[F-18] fluorodeoxyglucose (also known as FDG) andthe single-photon emitter Tc-99m SestaMIBI (also known as MIBI). FDG canbe detected with a positron emission tomography (also known as PET)scanner, or with a special device invented by the applying inventorknown as a positron emission mammography scanner. MIBI can be detectedwith a gamma camera, or with a special device invented by the applyinginventor known as a single photon emission mammography scanner. Severalinvestigators have used hand-held gamma cameras or non-imaging gamma raydetectors in an operating room to examine the patient's body prior toremoval of a cancer, and after removal of a cancer. No investigatorshave imaged the radioactive cancer after removal from the patient's bodyin order to assess whether the margins of resection were complete.

[0005] The present invention is novel in that it consists of the use ofa radiation detector in conjunction with surgically-resected humantumors, in situations where the patient was injected with thecancer-seeking radiotracer prior to surgery. After the human tumorspecimen is removed from the patient's body, it is either imaged whole(i.e., without slicing) or is sliced and then the slices imaged with theradiation detector. The radioactive tracer can either be a gamma emitterlike Tc-99m labeled SestaMIBI, or it can be a beta emitter like 2-(F-18)Fluorodeoxyglucose.

[0006] The present invention is also novel in that it allows comparativeimaging of the specimen by x-ray or other methods, and permitssimultaneous display of the radiotracer and the x-ray images.

[0007] Nobody has imaged a human surgical specimen from a patientinjected with radiotracers prior to surgery in order to describe thedistribution of tumor in the specimen, and specifically to determinewhether a tumor is wholly contained within the surgical specimen.Technically this approach is more easily accomplished than anintraoperative examination for several reasons: First, all the radiationis coming from the specimen when only the specimen is examined, whereasif we were to examine the tumor while it was in the patient we wouldhave to remove the influence of radiation from parts of the body otherthan the surgical specimen. In the case of breast imaging, this“scatter” from parts of the body other than the breast is much greaterthan the radiation emitted by the breast, which can make it verychallenging to see small tumors well.

SUMMARY OF THE INVENTION

[0008] The present invention provides surgeons with information as tothe extent and location of cancers or other pathological processesimmediately after removal of surgical specimens from the body. Thisinformation can help the surgeon decide whether the surgical procedurehas been adequate for removal of the patient's tumor, or whetheradditional tissues must be removed from the patient's body. The currentstandard of medical care is to employ staining methods that provide suchinformation several days after initial surgery, leading to the need foradditional (i.e., re-excision) surgery and anesthesia, whichinconveniences the patient and adds to health care costs. By providingearly information about the distribution of cancer in the tissuespecimen, the invention reassures the patient that initial surgery wasmost likely curative, and that no additional procedures are needed.Since the invention can rapidly assess whether cancer extends to themargins of the resected specimen, the surgeon can elect to keep thepatient on the operating room table while the pathologist inspects thespecimen with the invention. If the invention demonstrates that cancerextends to the margins of the specimen, the surgeon can remove moretissue without subjecting the patient to the need for a separatesurgical procedure (re-excision). The importance of the invention isillustrated by the fact that at centers of clinical excellence wheresurgeons perform lumpectomies for breast cancer, as many as a third oflumpectomies require re-excisions.

[0009] The present invention comprises an apparatus that is sensitive toa material which is administered to the patient prior to surgery, andwhich can be detected with the invention after removal of the surgicalspecimen. The material selectively accumulates in tumor cells, so thatimages of the surgical specimen with the invention provides informationabout the presence and distribution of tumor in the surgical specimen.The invention allows comparative anatomic images to be obtained of thesurgical specimen so that the surgeon can measure the distance betweentumor and the margin of the specimen. In this way the surgeon can assessthe likelihood that the specimen margin will be free of tumor.

[0010] A primary objective of the present invention is to describe thedistribution of cancer or precancerous conditions within a surgicalspecimen, for a patient who was injected with a substance prior tosurgery, which substance concentrates selectively in cancer orprecancerous cells (i.e., is tumor-seeking), said system preferablycomprising:

[0011] a detector sensitive to the substance which is present in thesurgical specimen and which selectively concentrates in the cancer orprecancer; and

[0012] an apparatus capable of forming an image based on the informationgathered by the detector, and which image describes the physicaldistribution of the substance in the surgical specimen rapidly so that asurgeon can be guided by the image provided by the apparatus; and

[0013] a holder capable of compressing the surgical specimen beforeand/or after slicing of the specimen against the detector so that thespatial resolution of the image is optimized.

[0014] A secondary objective of the invention is to compare thedistribution of tumor-seeking substance with other descriptive maps,such as x-ray attenuation, said system preferably comprising:

[0015] a detector sensitive to the substance which is present in thesurgical specimen and which selectively concentrates in the cancer orprecancer; and

[0016] an apparatus capable of forming an image based on the informationgathered by the detector, and which image describes the physicaldistribution of the substance in the surgical specimen rapidly so that asurgeon can be guided by the image provided by the apparatus; and

[0017] a holder capable of compressing the surgical specimen beforeand/or after slicing of the specimen against the detector so that thespatial resolution of the image is optimized; and

[0018] fiduciary markings upon the holder which are visible both on theimage of the tumor-seeking agent, as well as on other methods ofdescribing the distribution of tumor or anatomical information; and

[0019] a computer capable of using the fiduciary marker locations oneach image set to register the tumor-seeking image with other image setsand to combine these image sets in order to derive useful information.

[0020] The present invention pertains to a system for describing thephysical distribution of an agent that accumulates selectively in tissueof a patient in an excised surgical specimen. The system comprises anagent which selectively concentrates in a cancer or precancer or focusof infection or other pathological condition. The system comprises adetector sensitive to the agent which is present in the surgicalspecimen. The system also comprises an apparatus capable of forming animage based on the information gathered by the detector, and which imagedescribes the physical distribution of the agent in the surgicalspecimen so that a surgeon can be guided by the image provided by theapparatus, said apparatus connected to said detector.

[0021] The present invention pertains to a system for describing thephysical distribution of an agent that accumulates selectively in tissueof a patient in an excised surgical specimen. The system comprises anagent which selectively concentrates in a cancer or precancer or focusof infection or other pathological condition. The system comprises adetector sensitive to the agent which is present in the surgicalspecimen. The system comprises an apparatus capable of forming an imagebased on the information gathered by the detector, and which imagedescribes the physical distribution of the agent in the surgicalspecimen so that a surgeon can be guided by the image provided by theapparatus, said apparatus connected to said detector.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In the accompanying drawings, the preferred embodiment of theinvention and preferred methods of practicing the invention areillustrated in which:

[0023] FIGS. 1A-1H is a diagram of the preferred embodiment of theinvention as it would be employed in a typical patient study.

[0024]FIG. 2 is an image of the distribution of the radiotracer FDG asobtained in less than 20 minutes with an autoradiography device from asliced surgical specimen taken from a patient who had been injected withFDG prior to surgery.

[0025]FIG. 3 is a graph showing that the concentration of radiotracer inthe radiotracer images correlated with the presence of cancer precursorcells as determined by final pathological examination.

[0026]FIG. 4 is an x-ray image of the same sliced surgical specimenshowing that the x-ray can be used to provide additional informationabout the location of abnormal areas of accumulation seen on theradiotracer image.

[0027]FIG. 5 is a processed image in which the radiotracer image hasbeen divided by the x-ray image of the same sliced surgical specimen torender a rough idea of radiotracer concentration per cell of tissue.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0028] Referring now to the drawings wherein like reference numeralsrefer to similar or identical parts throughout the several views, andmore specifically to FIG. 1 thereof, there is shown a system fordescribing the physical distribution of an agent that accumulatesselectively in tissue of a patient in an excised surgical specimen. Thesystem comprises an agent which selectively concentrates in a cancer orprecancer or focus of infection or other pathological condition. Thesystem comprises a detector sensitive to the agent which is present inthe surgical specimen. The system comprises an apparatus capable offorming an image based on the information gathered by the detector, andwhich image describes the physical distribution of the agent in thesurgical specimen so that a surgeon can be guided by the image providedby the apparatus, said apparatus connected to said detector. system asdescribed in claim 1 including a holder for holding the surgicalspecimen against the detector so that the resolution of the image isoptimized, said holder attached to the detector.

[0029] Preferably, the system includes a holder for holding the surgicalspecimen against the detector so that the resolution of the image isoptimized. The holder attached to the detector. Preferably, the agent isa tumor seeking agent. Preferably, the system includes fiduciarymarkings or other recognizable features for determining the position andorientation of the specimens or specimen holder present upon the holderwhich are visible on the image of the tumor-seeking agent. Preferably,the system includes a computer which uses the fiduciary marker locationsor other recognizable features on each image to register thetumor-seeking image with other images and combines these images toidentify the presence and extent of cancer.

[0030] Preferably, the tumor-seeking agent is a radiotracer whichselectively accumulates in cancers or precancer conditions or focus ofinfection or other pathological condition, and where the detector issensitive to radiation from the radiotracer. Preferably, thetumor-seeking agent is a beta-emitting radiotracer which selectivelyaccumulates in cancers or precancer conditions, and where the detectoris sensitive to beta rays. Or, the tumor-seeking agent is a gamma-rayemitting radiotracer which selectively accumulates in cancers orprecancer conditions, and where the detector is sensitive to gamma rays.Or, the tumor-seeking agent is bromodeoxyuridine that after coupling toanother agent can distort electromagnetic fields, and which selectivelyaccumulates in cancers or precancer conditions, and where the detectoris sensitive to electromagnetic field perturbations.

[0031] The present invention comprises an apparatus 10 sensitive to thepresence and distribution of a given material which is present intissues that have been removed from the body after surgery, and whichwas administered to the patient (e.g., injected into a patient's vein,as in FIG. 1A) prior to surgery, and which selectively accumulates inmalignant cells (FIG. 1B). In one preferred embodiment, the givenmaterial is a radioactive substance that concentrates selectively incells with high metabolic activity, such as the radiotracer 2-[F-18]fluorodeoxyglucose. In this embodiment, the apparatus is sensitive tothe beta rays emitted by the F-18. The surgeon removes a piece of tissuecontaining a cancer, as in FIG. 1C. The surgical specimen is sliced bythe pathologist into thin (e.g., 3-mm thick) specimen slices, as is theusual practice today (as in FIG. 1D). Unlike the usual practice ofpathologists, which is to shave off sections of the specimen slices forrapid staining and viewing, the user of the introduces the additionalstep of placing the specimen slices on a gridded tray 20 (as in FIG.1E). The gridded tray 20 contains fiducial markers that are radio-opaqueto x-rays and also emit beta radiation. The pathologist places thedetector portion 25 in close proximity (or in contact) to the griddedtray 20 containing the specimen slices (as in FIG. 1F). The beta raysemitted by the slices of tissue are converted into electrical signals bythe detector portion 25, and the electrical signals are received asinput data by the computer portion 30, which processed the input data toform an image corresponding to the distribution of radioactive materialin the specimen slices (see FIG. 2). This distribution is related to thelocation of cancer precursor cells in the specimen slices (see FIG. 3).These results were obtained by having the pathologist analyze smallsections of the specimen, and grade the sections on the basis of thedegree to which the predominant tissue type in the sample resembledcancer cells (i.e., grade of 1 for fat cells, grade of 2 for normalbreast tissue, grade of 3 for sclerosing adenosis, grade of 4 fortypical hyperplasia, grade of 4 for atypical hyperplasia, grade of 5 forductal carcinoma in situ, grade 7 for invasive cancer). In FIG. 3, theabscissa represents the degree of dysplasia assigned for each smallsection (i.e., each data point represents one small section) by thepathologist. The ordinate represents the quantitative measurement ofradiotracer density in the tissue as measured with the beta-sensitiveapparatus. After the beta image has been collected, the gridded tray 20holding the specimens is taken to an x-ray camera 35 which provides amap of x-ray attenuation of the specimen slices (as in FIG. 1G, and FIG.4). Since the gridded tray 20 has an x-ray opaque grid and also hasfiducial markers that are visible both on the beta ray image as well asthe x-ray image, the beta ray image can be manipulated through imageprocessing techniques, as is well known in the art, so that thecoordinates of any location on the beta ray image are transformed intothe coordinate system of the x-ray image (as in FIG. 1H). The beta andx-ray images can then be displayed simultaneously (i.e., whereby thebeta image is a color overlay onto the x-ray image). This allows thepathologist to correlate his or her pathological findings with both thebeta ray image as well as the x-ray image. It is possible to use theadditional information provided by the x-ray image to enhance theutility of the beta ray image. For example, since the beta ray imageprovides a map of concentration of tumor-seeking radiotracer per unitarea, and the x-ray image describes roughly the number of cells per unitarea, dividing the beta ray image by the x-ray image gives the map ofconcentration of tumor-seeking radiotracer per unit cell, which may be amore robust indicator of malignancy than the radiotracer map alone.

[0032] In the alternative, there are devices in the market today whichare employed by physicians that use different tools to remove (i.e.,excise) tissue from the body. This class of tools are called minimallyinvasive technology. Autoradiographic agents can be injected prior tosuch procedures involving minimally invasive technology as well astraditional surgery. These devices generally use a tube (i.e., cannula)which cuts through tissue and removes a cylindrical plug.

[0033] One such device is the “Abbe” instrument, marketed by U.S.Surgical for biopsy of small breast cancers. This instrument can biopsya woman's breast while she is reclining on a table, with the breastprotruding through a cutout on the table. The Abbe tube removes a plugof tissue which can be sliced just as the surgical specimen is sliced inthe patent, and the slices placed within an autoradiographic imager asdescribed herein.

[0034] Another device applies suction through the cannula at the time ofbiopsy. The example of this device is the “Mammotome”, marketed byBiopsys, a subsidiary of Johnson and Johnson. The Mammotome removes a“stream” of tissue from the breast. The presence and quantity of theinjected agent is monitored in the stream as it is drawn out by thecannula, and also imaged in the specimens that have been removed by thecannula.

[0035] Although the invention has been described in detail in theforegoing embodiments for the purpose of illustration, it is to beunderstood that such detail is solely for that purpose and thatvariations can be made therein by those skilled in the art withoutdeparting from the spirit and scope of the invention except as it may bedescribed by the following claims.

What is claimed is:
 1. A system for describing the physical distributionof an agent that accumulates selectively in tissue of a patient in anexcised surgical specimen comprising: an agent which selectivelyconcentrates in a cancer or precancer or focus of infection or otherpathological condition; a detector sensitive to the agent which ispresent in the surgical specimen; and an apparatus capable of forming animage based on the information gathered by the detector, and which imagedescribes the physical distribution of the agent in the surgicalspecimen so that a surgeon can be guided by the image provided by theapparatus, said apparatus connected to said detector.
 2. A system asdescribed in claim 1 including a holder for holding the surgicalspecimen against the detector so that the resolution of the image isoptimized, said holder attached to the detector.
 3. A system asdescribed in claim 2 wherein the agent is a tumor seeking agent.
 4. Asystem as in claim 1 including fiduciary markings or other recognizablefeatures for determining the position and orientation of the specimensor specimen holder present upon the holder which are visible on theimage of the tumor-seeking agent.
 5. A system as in claim 4 including acomputer which uses the fiduciary marker locations or other recognizablefeatures on each image to register the tumor-seeking image with otherimages and combines these images to identify the presence and extent ofcancer.
 6. A system as in claim 1 where the tumor-seeking agent is aradiotracer which selectively accumulates in cancers or precancerconditions or focus of infection or other pathological condition, andwhere the detector is sensitive to radiation from the radiotracer.
 7. Asystem as in claim 6 including fiduciary markings or other recognizablefeatures which are present upon the holder which are visible on theimage of the tumor-seeking agent.
 8. A system as in claim 7 including acomputer which uses the fiduciary marker locations on each image toregister the tumor-seeking agent image with other images and combinesthese images to identify the presence and extent of cancer or focus ofinfection or other pathological condition.
 9. A system as in claim 1where the tumor-seeking agent is a beta-emitting radiotracer whichselectively accumulates in cancers or precancer conditions, and wherethe detector is sensitive to beta rays.
 10. A system as in claim 1including fiduciary markings or other recognizable features present uponthe holder which are visible on the image of the tumor-seeking agent.11. A system as in claim 4 including a computer which uses the fiduciarymarker locations on each image to register the tumor-seeking image withother images and combines these images to identify the presence andextent of cancer.
 12. A system as in claim 1 where the tumor-seekingagent is a gamma-ray emitting radiotracer which selectively accumulatesin cancers or precancer conditions, and where the detector is sensitiveto gamma rays.
 13. A system as in claim 1 including fiduciary markingsor other recognizable features present upon the holder which are visibleon the image of the tumor-seeking agent.
 14. A system as in claim 4including a computer which uses the fiduciary markings or otherrecognizable features on each image to register the tumor-seeking imagewith other images and combines these images to identify the presence andextent of cancer.
 15. A system as in claim 1 where the tumor-seekingagent is bromodeoxyuridine that after coupling to another agent candistort electromagnetic fields, and which selectively accumulates incancers or precancer conditions, and where the detector is sensitive toelectromagnetic field perturbations.
 16. A system as in claim 15including fiduciary markings or other recognizable features present uponthe holder which are visible on the image of the tumor-seeking agent.17. A system as in claim 16 including a computer which uses thefiduciary markings or other recognizable features on each image toregister the tumor-seeking image with other images and combines theseimages to identify the presence and extent of cancer.
 18. A system as inclaim 1 including fiduciary markings or other recognizable featurespresent upon the holder which are visible on the image of thetumor-seeking agent.
 19. A system as in claim 4 including a computerwhich uses the fiduciary marker locations on each image to register thetumor-seeking image with other images and combines these images toidentify the presence and extent of cancer.
 20. A system as described inclaim 1 wherein the fiduciary markers or other recognizable features arealso visible on an x-ray image or on an image of the specimen obtainedwith visible light.
 21. A method for describing the physicaldistribution of an agent that accumulates selectively in tissue of apatient in an excised surgical specimen comprising the steps of: placingthe specimen with an agent in a holder; and detecting with an agent acancer or precancer or focus of infection or other pathologicalcondition.